FSU ETD TemplateANIONIC REARRANGEMENT OF 2-BENZYLOXYPYRIDINE DERIVATIVES AND A
SYNTHETIC APPROACH TO ALDINGENIN B
By
A Dissertation submitted to the Department of Chemistry and Biochemistry
in partial fulfillment of the requirements for the degree of
Doctor of Philosophy
Degree Awarded: Spring Semester, 2011
The members of the committee approve the dissertation of Jingyue Yang defended on March 17,
2011.
_______________________________________ Gregory B. Dudley Professor Directing Dissertation
_______________________________________ Thomas C. S. Keller ΙΙΙ University Representative _______________________________________ Igor Alabugin Committee Member _______________________________________ Lei Zhu Committee Member
_______________________________________ Michael Shatruk Committee Member
Approved: _____________________________________ Joseph B. Schlenoff, Chair, Department of Chemistry and Biochemistry
The Graduate School has verified and approved the above-named committee members.
ii
This manuscript is dedicated to my mother, father, brother and all my friends who supported me all the time.
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ACKNOWLEDGEMENTS
First of all, I would like to acknowledge Professor Gregory Dudley, without whom I
could not have achieved what I have today. From him, I learned not only new ideas and
information, but also how to properly conduct research. The way he teaches is not by giving a
simple answer, but by guiding us to the right path and making us find the answer. Gradually, I
learned to do research more and more independently. Personally, I would like to thank Professor
Gregory Dudley again. As a young international graduate student, I joined his group with many
questions about chemistry as well as the life in the United States. He was always accessible and
helpful with all of my questions. More recently, we spoke about my future career plans: his
advice, using his own experiences from starting his own career, is invaluable. Dr. Dudley not
only made me an independent scientist, but has also prepared me to start my career as an
independent scientist. For everything he has done, I will always be grateful.
I would also like to thank the group members of the Dudley lab: Dr. Sreenivas
Katakojvala, who helped me to set up my hood and start my graduate research; Dr Jumreang
Tummatorn, Dr. Philip A. Albiniak, Dr. Jeannie H. Jeong, Dr. David M. Jones, Dr. Douglas A.
Engel, Dr. Mariya V. Kozytska and Dr. Sami Fahd Tlais, who helped me greatly during my time
at the Florida State University, providing many useful suggestions for my research; Rimantas
Slegeris, who provided several intermediates for my aldingenin research; Apiwat (Chern)
Wangweerawong, who helped with my [1,2]-rearrangement project; Marilda Lisboa, Michael R.
Rosana, Tung Thanh Hoang, Paratchata (Tae) Batsomboon and Ron Ramsubhag, who always
accompanied me in the lab as friends and colleagues.
I would like to thank my family and friends who supported and helped me in these past
five years. Mom, dad, Yangyang and Yuhang, thank you for your never ending support. Thanks
to Grace, Huanyu, Sha, Yuhua, Xiaozhao, Jingfang and all the other great friends in my life.
Thanks to Kerry Gilmore and Abdulkader Baroudi for helping with the editing work and
calculation studies.
I would also like to thank all my committee members: Dr. Gregory Dudley, Dr. Igor
Alabugin, Dr. Lei Zhu, Dr. Michael Shatruk, Dr. Thomas C. S. Keller III — thank you for all of
your valuable suggestions. Finally, I would like to thank all of those who helped me edit this
manuscript: Michael R. Rosana, Brian Ondrusek and Professor Dudley.
List of Tables .......................................................................................................... vii List of Figures ........................................................................................................ viii Abstract ................................................................................................................... xii PART 1. ANIONIC REARRANGEMENT OF 2-BENZYLOXYPYRIDINE DERIVATIVES CHAPTER 1: BACKGROUND OF [1,2] –ANIONIC REARRANGEMENTS..1
1.1 [1,2]-Wittig Rearrangement .......................................................................2 1.2 [1,2]-Brook Rearrangement........................................................................5
2.1 Introduction: Known chemistry of BnOPyr ...............................................8 2.1.1 Benzylation of alcohols by 2-benzyloxy-1-methylpyridinium triflate (Bn-OPT) ................................................................................................8 2.1.2 Benzylation of carboxylic acids by 2-benzyloxy-1- methylpyridinium triflate (Bn-OPT) .................................................................9 2.1.3 Benzylation of alcohols by methylation of 2-benzyloxypyridine .........................................................................................10 2.2 Discovery of the reaction..........................................................................11 2.3 Development of the reaction (Optimization & Scope).............................12 2.4 Application of the reaction (Synthesis of Carbinoxamine)......................17
CHAPTER 3: EXPERIMENTAL: [1,2]-ANIONIC REARRANGEMENTS OF 2-BENZYLOXYPYRIDINE DERIVATIVES........................................................19
CHAPTER 4: AN ALTERNATIVE ENTRY INTO THE ANIONIC REARRANGEMENT OF BEZYLOXYPYRIDINES---PYRIDINE-DIRECTED ORGANOLITHIUM ADDITION TO AN ENOL ETHER ....................................53
4.1 The chemistry of enol ethers ....................................................................54 4.2 Overview of the new pyridine directed organolithium addition to enol ether 7................................................................................................................55
v
CHAPTER 5: EXPERIMENTAL: PYRIDINE-DIRECTED ORGANOLITHIUM ADDITION TO AN ENOL ETHER ....................................64
CHAPTER 6: FUTURE PLANS ........................................................................98
PART 2. A SYNTHETIC APPROACH TO ALDINGENIN B CHAPTER 7: INTRODUCTION........................................................................99
7.1 Addition/ fragmentation of vinylogous acyl triflates (VATs)..................99 7.2 Carbonyl extrusion of dihydropyrone (DHP) triflates to yield homopropargyl alcohols .................................................................................101 7.3 Isolation of aldingenin B ........................................................................103 7.4 Retrosynthetic analysis of aldingenin B .................................................104 7.5 Oxidative ketalization of alkynes ...........................................................106
CHAPTER 8: SYNTHESIS TOWARDS THE TRICYCLIC CORE OF ALDINGENIN B ...................................................................................................110 8.1 Model study---test of the oxidative ketalization step .............................110
8.2 Synthesis of the alkyne-diol 2a for the oxidative ketalization...............111 8.3 Oxidative keto-ketalization on alkyne-diol 2a .......................................113
CHAPTER 9: PRELIMINARY EXPERIMENTS TO GUIDE FUTURE EFFORTS...............................................................................................................115
CHAPTER 10: EXPERIMENTAL: A SYNTHETIC APPROACH TO
ALDINGENIN B ...................................................................................................121
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xii
ABSTRACT
[1,2]-Anionic rearrangements are important tools for altering the complexity of
molecules at hand. In Part I of this dissertation, an anionic rearrangement of 2-benzyloxypyridine
is described. Pyridine-directed metallation of the benzylic carbon leads to 1,2-migration of
pyridine via a postulated associative mechanism (addition / elimination). Several aryl pyridyl
carbinols were obtained in high yields. A formal synthesis of carbinoxamine, an
antihistamine drug used for the treatment of seasonal allergies and hay fever, emerges from
this methodology. As an update, the [1,2]-anionic rearrangement of benzyl 2-pyridyl ethers
can also be accessed by a distinct and unusual mechanism: addition of alkyllithium reagents
to α-(2-pyridyloxy)-styrene triggers anionic rearrangement to teriary pyridyl carbinols. This
will be presented in Chapter 4 and the process is explained by invoking contraelectronic,
pyridine-directed carbolithiation of the enol ether π-system.
Part II of this dissertation is focused on a synthetic approach to aldingenin B. The
synthesis of the tricyclic core of aldingenin B from a key internal alkyne was completed.
Synthesis of alkynes by fragmentation is an on-going interest of the Dudley lab. One current goal
is to apply our methodology in conjunction with an innovative oxidative alkyne ketalization to
achieve a short and efficient synthesis of aldingenin B. The specific goal for this dissertation was
to prepare a model alkyne by conventional methods and establish the feasibility of the oxidative
alkyne ketalization. The preparation and selenium-mediated cyclo-ketalization of an alkyne-diol
will be described as a model study for the synthesis of aldingenin B in Chapter 8. The oxidative
cyclization is a simplifying transformation for aldingenin B, as it provides a convenient method
for generating the tricyclic core of the natural product from a functionalized carbocycle. Some
preliminary experiments to guide future efforts for completing the synthesis of aldingenin B will
be presented in Chapter 9.
PART 1: ANIONIC REARRANGEMENT OF 2-
BENZYLOXYPYRIDINE DERIVATIVES
CHAPTER ONE
BACKGROUND OF [1,2] –ANIONIC REARRANGEMENTS
[1,2]-Anionic rearrangements, such as those pioneered by Wittig 1 and Brook 2 , are
important tools for altering the complexity of molecules. Rearrangement reactions interconvert
pairs of structural isomers; this interconversion is especially valuable if one of the two isomers is
more accessible than the other. Parallels can be drawn between the Wittig and Brook reactions as
well as the new anionic rearrangement of pyridyl ethers discovered in our lab (Figure 1). This
new [1,2]-anionic rearrangement of 2-benzyloxypyridine derivatives will be discussed in this
manuscript after a brief introduction of the [1,2]-Wittig rearrangement and [1,2]-Brook
rearrangement.
1
1.1 [1,2]-Wittig Rearrangement
In 1942, Georg Wittig and Lisa Lhman reported the migration of an alkyl group from an
oxygen center to the α-carbanion center in the isomerization reaction of a benzylic ether with
phenylithium (Figure 2, Equation 2a).1 This is the first example of the Wittig rearrangement,
which involves conversion of an α-alkoxy-carbanion into a more stable oxyanion with
concomitant migration of the alkyl group. While studying this new rearrangement reaction, it
was found that the rearrangement of allylic ethers can follow a different pathway (Figure 2,
Equation 2b). This [2,3]-sigmatropic version of the carbanion rearrangement is now called the
[2,3]-Wittig rearrangement3, while the original is often called the [1,2]-Wittig rearrangement4.
Figure 2: [1,2]-Wittig Rearrangement and [2.3]-Wittig Rearrangement
Experimental evidence generally points to a stepwise, dissociative mechanism for the
[1,2]-Wittig rearrangement. The mechanism involves carbon-oxygen-bond homolysis and
recombination of the resulting pair of intermediate radicals (cf. Figure 1, Scheme 1A).5 In the
1960s, Schllkopf and co-workers observed that the optically active benzyl 2-butyl ether and
benzyl 2-phenyl-2-butyl ether afforded the corresponding alcohol products with retention of
configuration in 20% and 80% enantiomeric excess, respectively (Figure 3). 6 This finding
further supports a dissociative mechanism.
2
Figure 3: Partial Racemization of the [1,2]-Wittig Rearrangement of Optically Active Benzyl Ethers
In order to illustrate the scope and limitation of the [1,2]-Wittig rearrangement, the Nakai
group designed a series of reactions using tin/lithium trans-metalation to induce the
rearrangement of various ethers.7 They first employed a propyl group as the carbanion terminus
(R=C2H5, Figure 4, Equation 4b) and a benzyl group as the migrating group (R’=Bn, Figure 4,
Equation 4b) in the Wittig reaction and obtained the rearrangement product in 90% yield (Figure
4, Equation 4b). This is in contrast to the observation that the Still group found8, which was that
no rearrangement occurred when the carbanion terminus was a methyl group (R’=H, Figure 4,
Equation 4c). Instead of the Wittig product, the Still group only obtained the addition product of
the initial carbanion without rearrangement by quenching the reaction with cyclohexanone
(Figure 4, Equation 4c). It indicates that in [1,2]-Wittig rearrangement, the secondary carbanion
terminus is more reactive than the primary carbanion terminus. However, even with a secondary
carbanion terminus (R=C7H15, Figure 4, Equation 4d), the isopropyl ether did not rearrange
(Figure 4, Equation 4d). The comparison between equations 4c and 4d in Figure 4 shows that the
benzyl group is a better migrating group than isopropyl group. The last two reactions that the
Nakai group used to define the structure requirements were carried out on two tetrahydrofuranyl
ethers (Figure 4, equation 4e & 4f). For the two tetrahydrofuranyl ethers with a benzylic
carbanion terminus (R=Ph, Figure 4, Equation 4e), the rearrangement product was observed; in
contrast, with a propyl group as the counterpart (R=C2H5, Figure 4, Equation 4f), no
rearrangement product was observed. These two reactions indicate that a benzylic carbanion
terminus has higher reactivity in Wittig rearrangement than secondary carbanion terminus.
All of these observations reveal that [1,2]-Wittig rearrangement requires at least one, if
not both, of the radical-stabilizing factors in either the carbanion terminus or the migrating
group. The migratory aptitude of the R’ group decreases in the following order: benzyl > tertiary
alkyl > secondary alkyl > primary alkyl; while the migratory aptitude of the carbanion terminus
3
decreases in the same order: benzylic carbanion terminus > secondary carbanion terminus >
primary carbanion terminus.
Wittig rearrangement
BnO C2H5
SnBu3 n-BuLi
R=C2H5, R'=Bn
R=H, R'=Bn
R=C7H15, R'=i-Pr
R=Ph, R'=tetrahydrofuranyl
R=C2H5, R'=tetrahydrofuranyl
Figure 4: Study for the Scope Of the [1,2]-Wittig Rearrangement by Nakai
The [1,2]-Wittig rearrangement provides insight into the reactivity profile of reactive
carbanion intermediates, but its value in synthesis9 is limited due to difficulties associated with
guiding complex molecular systems along the high-energy radical reaction pathway. As a result,
4
there are only a few examples of the purely synthetic application of the [1,2]-Wittig
rearrangement. In 1987, Schreiber and co-workers employed the [1,2]-Wittig rearrangement in
the synthesis of syn-1,3-diol monoethers from β-alkoxyalkyl allyl ethers. The syn-1,3-diol
products were obtained in 14-32% yield with 90-95% diastereoselectivity (Figure 5). 10
Figure 5: Synthetic Application of the [1,2]-Wittig Rearrangement
1.2 [1,2]-Brook Rearrangement
In the [1,2]-Brook rearrangement,11 it is a silyl group that migrates between the carbinol
center to the adjacent oxygen atom (Figure 6). The R group can be either alkyl or aryl groups and
various trialkyl silyl groups rearrange (SiMe3, SiEt3, SiMe2t-Bu, etc.). Silyl migration is
reversible (see the retro-Brook 12 reaction) and likely proceeds via a pentavalent silicate
intermediate. The first retro-Brook reaction was reported by Speier in 195313 with later studies
by West et al12.
Figure 6: [1,2]-Brook Rearrangement and Retro-Brook Rearrangement
In order to elucidate the mechanism of the retro-Brook rearrangement, Linderman and
Ghannam designed several reactions on different stannanes.14 In these reactions, transmetalations
5
occurred first and the rearrangement was driven by the formation of the more stable lithium
alkoxide. The Linderman group showed that the retro-Brook reaction is an intramolecular
process by carrying out a cross-over experiment (Figure 7). A 1 : 1 mixure of two stannanes
were treated with 3 equiv. of butyllithium at -78 °C. The reaction was complete for both starting
materials after 15 minutes and only the two intramolecular products were obtained in high yields.
By GC analysis of the crude reaction product mixture, no trace amount of any cross-over product
was observed.
Figure 7: Evidence for an Intramolecular Process of the Retro-Brook Rearrangement
Linderman and Ghannam also found evidence to support the conclusion that the
rearrangment reaction does not involve radical intermediates in the reaction pathway. A
cyclopropyl-substituted stannane was synthesized for this purpose (Figure 8). Cyclopropyl-
substitued radicals rapidly undergo ring opening reactions.15 If there are radical intermediates
invovled in the reaction pathway in the retro-Brook rearrangement, the cyclopropyl ring is easily
opened to yield an enol ether as the product. However, only the alcohol product was observed in
45% yield. Both GC and MS analysis showed no trace amount of the enol ether product.
6
Figure 8: Evidence for No Radical Intermediates Involved in the Retro-Brook Rearrangement
Recently, the retro-Brook rearrangement has received renewed interest, in part due to
acylsilane methodologies that produce α-silyl alcohol substrates for the [1,2]-Brook reaction.16
One of the synthetic applications for the retro-Brook rearrangement is the synthesis of optically
active (α-hydroxyalkyl)alkylsilanes (Figure 9).14 The synthesis started from the enantioselective
reduction of a hexanal, followed by TMS protection. The retro-Brook rearrangement reaction
finally provided the α-silyl alcohol product in 91% yield and 97% ee. The rearrangement
occurred with retention of configuration and without racemization.
C5H11 SnBu3
O (R)-(+)-BINAL
C5H11 SnBu3
OH H
C5H11 SiMe3
OH H
7
NEW [1, 2]-ANIONIC REARRANGEMENT OF 2-
BENZYLOXYPYRIDINE DREVATIVES
2-Benzyloxypyridine is readily available from coupling 2-chloropyridine with the
potassium salt of benzyl alcohol in refluxing toluene.17 It can be methylated with methyl triflate
in toluene to yield 2-benzyloxy-1-methylpyridinium triflate (Bn-OPT), which is a commercially
available benzylation reagent patented by the Dudley group (Figure 10). This triflate salt is a
white crystalline solid, which is stable to be stored at room temperature. It can be used to protect
alcohols as benzyl ethers or carboxylic acids as benzyl esters under mild conditions.
Figure 10: Synthesis of 2-Benzyloxy-1-methylpyridinium Triflate (Bn-OPT)
2.1.1 Benzylation of alcohols by 2-benzyloxy-1-methylpyridinium triflate (Bn-OPT)
Solutions of 2-benzyloxy-1-methylpyridinium triflate (Bn-OPT) with primary, secondary,
or tertiary alcohols under mild heating gave rise to the corresponding benzyl ethers. The best
condition developed for the efficient benzylation is to stir the mixture in PhCF3 at 83 ºC for 24 h
8
(Figure 11).18a-c, 18f The typical acid scavenger added to the reaction mixture is magnesium oxide.
The yields of the benzylation reactions are generally above 80%.
O N
R OBn
Figure 11: Benzylation of Alcohols by 2-Benzyloxy-1-Methylpyridinium Triflate (Bn-OPT)
2.1.2 Benzylation of Carboxylic acids by 2-benzyloxy-1-methylpyridinium triflate (Bn-OPT)
After being recognized as a successful benzyl transfer reagent, 2-benzyloxy-1-
methylpyridium triflate (Bn-OPT) was then used to prepare benzyl esters from carboxylic
acids.18d,f The conditions optimized for benzylating alcohols were first employed for the
benzylation of carboxylic acids, but MgO was proved to be a poor acid scavenger. Actually, the
reaction results were better (fewer byproducts) in the absence of MgO added. After a brief
screening of different bases, it was found that triethylamine (Et3N) provided complete
conversion to benzyl esters from carboxylic acids, and the formation of the byproduct (Bn2O)
was completely suppressed (Figure 12). As a result, the optimized condition, which was to heat a
PhCF3 solution of carboxylic acid with 2-benzyloxy-1-methylpyridium triflate and triethylamine
(Et3N) at 83 ºC for 24h, gave the corresponding benzyl esters in 81-99% yield.
9
RCO2Bn
Figure 12: Benzylation of Carboxylic Acids by Benzyloxypyridinium Triflate (Bn-OPT)
2.1.3 Benzylation of alcohols by methylation of 2-benzyloxypyridine
As mentioned above, 2-benzyloxypyridine can be converted into 2-benzyloxy-1-
methylpyridinium triflate for use as a benzyl transfer reagent. It can also be used directly to
protect alcohols.18e,f The Dudley group provided a revised benzyl transfer protocol for alcohols,
in which N-methylation of 2-benzyloxypyridine produced the active benzyl transfer reagent
in situ (Figure 13). The new protocol is as follows: a mixture of the alcohol substrate, 2-
benzyloxypyridine and magnesium oxide in toluene was cooled to 0 °C and treated with methyl
triflate. The resulting reaction mixture was allowed to warm up to room temperature and then
heated at 90 °C for 24 h. The yields for this one-step protocol were comparable to those using 2-
benzyloxy-1-methylpyridinium triflate as the benzyl transfer reagent. Trifluorotoluene was the
preferred solvent and it was uniquely effective in one case, although toluene was an appropriate
solvent for most cases.
10
After the introduction about the known chemistry of 2-benzyloxypyridine, we will talk
about how the new [1,2]-anionic rearrangement was discovered while we studied the synthetic
chemistry of 2-benzoxypyridine.
The novel [1,2]-anionic rearrangement of 2-alkoxypyridines (Figure 14) was identified
while studying the synthetic chemistry of 2-benzyloxypyridine (1a, Figure 15) as part of our
interest in developing electrophilic reagents for the synthesis of arylmethyl ethers and esters.19
We had envisioned making derivatives of 1a via directed metalation using the complex-induced
proximity effect (CIPE),20 followed by trapping with electrophiles (1a 3 4, Figure 15, not
observed). Instead, prior to addition of the electrophile, we observed an unexpected product:
phenyl-(2-pyridyl)-methanol (2a, Figure 15).
NO
Li
Ph
Figure 15: Discovery of the Anionic Rearrangement of 2-Benzoxypyridine 1a
11
Rearrangement of benzyllithium 3 accounts for the formation of α-pyridyl alcohol 2a.
The mechanism likely involves an associative process, akin to the Brook pathway, in which the
migrating carbon atom transiently expands to a tetrahedral (sp3) intermediate (cf. 5, Scheme 15)
that is hypervalent relative to the trigonal planar (sp2) ground state structure. Complexation
between the pyridine nitrogen and the lithium ion is maintained throughout the nucleophilic
aromatic substution (addition / elimination) of the electron-deficient pyridine ring. Related
[1,2]-anionic rearrangements of α-carbamoyloxy-carbanions (from directed metallation of
carbamates) are known,21 as is the [1,4]-migration of pyridine rings onto urea-derived α-amino-
carbanions.22
2.3 Development of the reaction (Optimization & Scope)
α-Pyridyl alcohols (2) are of general interest in synthesis and medicinal chemistry.23 For
example, the Ducharme group has synthesized different 2-pyridinemethanol derivatives as a
novel series of phosphodiesterase-4 (PDE4) inhibitors, which can be used for the treatment of
asthma, chronic obstructive pulmonary disease (COPD) and atopic dermatitis.24 The α-pyridyl
alcohol bellow (Figure 16) has been shown to exhibit excellent in vitro activity and good
efficacy in guinea pig and sheep models of bronchoconstriction. In order to gain access to
different α-pyridyl alcohols, the [1,2]-anionic rearrangement pathway can be employed. To the
best of our knowledge, the [1,2]-anionic rearrangement of 2-alkoxypyridines has not been
observed previously.25
12
Key experiments related to identifying optimal conditions for the n-butyllithium-promoted
rearrangement of 2-benzyloxypyridine are recounted in Table 1. The efficiency of the reaction is
highly sensitive to minor changes in the reaction protocol. Full conversion requires a slight molar
excess of n-BuLi (1.2 equiv), but too much base is detrimental (Table 1, Entries 1–3 and 7). In
order to understand this result better, MeOD was used to quench the reaction. When using
specifically 1.2 equiv of n-BuLi, a reaction temperature of –60 °C provides results superior to
slightly higher or lower reaction temperatures (Table 1, Entries 4–6). Optimally, treatment of
2-benzyloxypridine (1a) in THF i with 1.2 equiv of n-BuLi at –60 °C furnishes phenyl-
(2-pyridyl)-methanol (1a 2a) in 85% yield (Table 1, entry 5). The delicate balance of reaction
conditions required for optimal results is indicative of a complicated reaction pathway. It appears
that n-BuLi competitively metallates both the substrate and the product.ii
i A brief screening of other solvents and/or co-solvents — Et2O, toluene, hexane, HMPA, DMPU
— failed to identify a superior option. ii Deuterium is incorporated to a minor extent into the product alcohol (at the carbinol carbon)
when the reaction is quenched with MeOD. Thus, in situ-metalation of the product must be
occuring, which consumes n-butyllithium and explains the need for a precise excess of
n-butyllithium for optimal results.
O N
1 1.1 equiv –78°C to rt 5–10% n.d.
2 1.2 equiv –78°C to rt —b 77%
3 2.0 equiv –78°C to rt —b n.d. c
4 1.2 equiv –78 °C 42% n.d.
5 1.2 equiv –60 °C —b 85%
6 1.2 equiv –40 °C 17% n.d.
7 1.3 equiv –60 °C —b 77%
a Estimated by 1H NMR spectroscopy. b Complete consumption of 1a. c Significant decomposition was apparent in the TLC analysis of the reaction mixture.
Changing the substrate from 2-benzyloxypyridine to related derivatives changes the
kinetic profile of the reaction; the conditions described in entry 5 of Table 1 are not generalizable
(Table 2). For example, the reaction conversion drops significantly for methoxy-substituted
ethers 1b and 1c, likely due to competing metallation pathways, although the yields of 2 based
on recovered starting material remain high (estimated >95%, Table 2, Entries 1 and 2).
α-Branching in 1d was detrimental in other ways (Table 2, Entry 3): conversion to tertiary
alcohol 2d was incomplete, and a new by-product emerged, resulting from addition of
n-butyllithium to the pyridine ring.iii
iii The byproduct was determined to be 2-butyl-6-(1-phenyl-ethoxy)-pyridine (shown below),
from addition of n-butyllithium to the pyridine ring followed by autoxidation.
14
Table 2. Substituent Effects and An Alternative Set of Conditions for Promoting the [1,2]- Anionic Rearrangement
Ar OH
reflux, 2 h (yield of 1)
Ar O Ar
R OH N
1 2
entry Ar R Yield of 1 base Temp Yield of 2
1 2-MeO-C6H4 H 90% (1b) n-BuLi –60 °C 48% a (2b)
2 4-MeO-C6H4 H 92% (1c) n-BuLi –60 °C 33% a (2c)
3 C6H5 Me 96% (1d) n-BuLi –60 °C to rt 24% b (2d)
4 C6H5 Me 96% (1d) LDA c rt 95% (2d)
a Mass balance was recovered starting material (52% of 1b and 67% of 1a). b Starting material and undesired by-products recovered. c 1.3 equiv of LDA employed.
Rather than attempt to re-optimize the reaction protocol for each substrate (1 2)
individually, a unified set of conditions with applicability across a broader range of substrates
was sought. Lithium diisopropylamide (LDA) was the preferred choice from among severaliv
potential bases (Table 2, entry 4).
iv The bases included s-BuLi, t-BuLi, PhLi, BnLi, Ph3CLi, LDA, LiHMDS, LiDMSO,
LiN(OMe)Me, LiTMP, LiH, and alkyl Grignard reagents. LDA was sufficiently reactive to
promote the rearrangement, and no competing addition to the pyridine ring was observed. After
brief optimization (not shown) and screening against multiple substrates, 1.3 equiv of LDA at rt
emerged as the optimal set of conditions.
15
Table 3. Scope and Limitations of the LDA-promoted [1,2]-Anionic Rearrangement of Arylalkoxypyridines
Ar OH
reflux, 2 h (yield of 1)
Ar O Ar
R OH N
1 2
1 C6H5 H 95% (1a) 98% (2a)
2 2-MeO-C6H4 H 90% (1b) 99% (2b)
3 4-MeO-C6H4 H 92% (1c) 99% (2c)
4 4-CF3-C6H4 H 75% (1e) 0%
5 4-Cl-C6H4 H 93% (1f) 70% (2f)
6 C6H5 Me 96% (1d) 95% (2d)
7 C6H5 Et 96% (1g) 86%a (2g)
8 C6H5 Cyb 63% (1h) 20%a (2h)
9 C6H5 t-Bu 57% (1i) 0%a
10 C6H5 Ph 99% (1j) 97% (2j)
a Mass balance was recovered starting material (1). b Cy = cyclohexyl
The reaction conditions involving LDA as the base instead of n-BuLi were then used to
explore the scope of the rearrangement reaction (Table 3). The title substrate
(2-benzyloxypyridine, 1a) rearranged to 2a in 98% yield (Table 3, Entry 1). Electron-donating
groups on the benzene ring are well tolerated: rearrangement of substrates with either an
ortho-methoxy (1b) or para-methoxy (1c) substituent proceeded each in 99% yield (Table 3,
Entries 2 and 3). The yield of 2 decreased to 70% when the electron-withdrawing para-chloro
substituent was in place (1f 2f, Table 3, Entry 5), and para-trifluoromethylated substrate 1e
decomposed under the reaction conditions (Table 3, Entry 4).
For making tertiary -pyridyl alcohols (Table 3, Entries 6–10), the anionic rearrangement
seems to depend on whether or not metallation occurs. Sterics and kinetic acidity play an
16
important role (Table 3, Entries 6–9); the reaction conversion of alkyl-substituted pyridyl ethers
and the isolated yield of the -pyridyl alcohol relate inversely to the size of the branching
substituent at the benzylic ether position. The relevance of thermodynamic acidity can be
inferred from entry 10; 2-(diphenylmethoxy)-pyridine (1j), presumably the most acidic of the
substrates included in Table 3, furnishes tertiary alcohol 2j in 97% yield.
2.4 Application of the reaction (Synthesis of Carbinoxamine)
-Pyridyl alcohol ()-2f (see Table 3, entry 5) has been converted in one step into
()-carbinoxamine26 (Figure 17), the resolution of which is accomplished using d-tartaric acid.27,
28 Carbinoxamine is an antihistamine drug (histamine H1 antagonist) used for the treatment of
seasonal allergies and hay fever.29
OH
N
Cl
In conclusion, a [1,2]-anionic rearrangement of 2-benzyloxypyridine and its derivatives is
reported. According to our postulated mechanism, pyridine-directed metallation at the benzylic
position triggers an intramolecular nucleophilic aromatic substitution reaction (addition /
elimination) via an intermediate spiroepoxide (5, Figure 15). This new discovery provides a link
between two disparate reaction pathways: the [1,2]-Wittig rearrangement (in which arene
migration is rare) and the tandem directed metallation / nucleophilic acyl substitution
methodologies developed by Snieckus, Gawley, Clayden, and others.21,22 Pyridyl ethers 1 are
17
readily available from the corresponding alcohols and 2-chloropyridine. A variety of secondary
and tertiary -pyridyl alcohols were prepared in good to excellent yield.
18
BENZYLOXYPYRIDINE DERIVATIVES
General information
1H-NMR and 13C-NMR spectra were recorded on a 300 MHz spectrometer using CDCl3 as the
deuterated solvent. The chemical shifts (δ) are reported in parts per million (ppm) relative to
internal TMS (0 ppm for 1H NMR) or the residual CDCl3 peak (7.26 ppm for 1H NMR, 77.0 ppm
for 13C NMR). The coupling constants (J) are reported in Hertz (Hz). IR spectra were recorded
on an FT-IR spectrometer from PerkinElmer. Mass spectra were recorded using electrospray
ionization (ESI) or electron ionization (EI) techniques. All chemicals were used as received
unless otherwise stated. Cyclohexyl-(phenyl)methanol30 , tert-butylphenylcarbinol31, 1-phenyl-1-
buten-3-ol32 were prepared using reported procedures. The solvents used for the reactions were
all freshly distilled. Glassware, NMR tubes, stir bars, needles, and syringes were dried overnight
in an oven heated at 120 °C. All reactions were performed under argon atmosphere unless
otherwise noted. Neutral organic compounds were purified by flash column chromatography
using silica gel F-254 (230-499 mesh particle size).Yields refer to isolated material judged to be
>95% pure by 1H NMR spectroscopy.
General experimental procedures
Etherification: We prepared benzyloxypyridines 1 by a modified version of a procedure first
reported in 1980:33 A toluene solution of the appropriate benzyl alcohol derivative (500 mg, 0.5
M, 1.0 equiv), the corresponding 2-chloropyridine derivative (1.1 equiv), KOH (3.3 equiv), and
18-crown-6 (0.05 equiv) were heated at reflux until all of the alcohol was consumed. The
resulting mixture was cooled to room temperature and then diluted with H2O (20 mL). The
19
mixture was extracted with EtOAc (4 x 15 mL). The combined organic extract was washed with
H2O until the aqueous layer becomes neutral, then with brine and dried (Na2SO4), filtered,
concentrated under vacuum, and purified on silica gel to yield benzyloxypyridines 1.
[1,2] Anionic rearrangement by n-BuLi: To a solution of benzyloxypyridines 1 (100 mg, 1.0
equiv) in THF (1 mL) at –60 °C was added n-BuLi (1.2 equiv) dropwise, and the solution was
stirred at that temperature for 2 h before being quenched with MeOH. The resulting mixture was
warmed up to room temperature and then diluted with H2O (5 mL). The mixture was extrated
with EtOAc (4 x 5 mL). The combined organic extract was then washed with brine, dried
(Na2SO4), filtered, concentrated under vacuum, and purified on silica gel to yield pyridine
alcohols 2.
[1,2] Anionic rearrangement by LDA: To a solution of LDA (1.3 equiv) in THF at room
temperature was added benzyloxypyridines 1 (100 mg, 1.0 equiv) in THF (1 mL) dropwise, and
the solution was stirred over night or until all the starting material was consumed. The resulting
mixture was diluted with H2O (5 mL), then extrated with EtOAc (4 x 5 mL). The combined
organic extracts were then washed with brine, dried (Na2SO4), filtered, concentrated under
vacuum, and purified on silica gel to yield pyridine alcohols 2.
Characterization Data
2-Benzyloxypyridine (1a); yellow oil (95%); 1H NMR (300 MHz, CDCl3) δ 8.18 (dd, J=5.06,
1.94 Hz, 1H), 7.61-7.55 (m, 1H), 7.48-7.25 (m, 5H), 6.88 (dd, J=7.07, 5.11 Hz, 1H), 6.81 (d,
J=8.37 Hz, 1H), 5.38 (s, 2H).
20
NO
OMe
2-[(2-Methoxyphenyl)methoxy]-pyridine (1b); white crystals (90%); 1H NMR (300 MHz,
CDCl3) δ 8.20 (dd, J=4.99, 1.44 Hz, 1H), 7.61-7.55 (m, 1H), 7.47 (d, J=7.35, 1H), 7.33-7.27 (m,
1H), 6.99-6.81 (m, 4H), 5.42 (s, 2H), 3.86 (s, 3H).
2-[(4-Methoxyphenyl)methoxy]-pyridine (1c); yellow oil, (92%); 1H NMR (300 MHz, CDCl3)
δ 8.18 (dd, J=5.07, 1.30 Hz, 1H), 7.57 (ddd, J=8.44, 7.09, 2.01 Hz, 1H), 7.40 (d, J=8.72, 2H),
6.94-6.86 (m, 3H), 6.78 (d, J=8.37, 1H), 5.30 (s, 2H), 3.82 (s, 3H).
2-(1-Phenylethoxy)-pyridine (1d); yellow oil, (96%); 1H NMR (300 MHz, CDCl3) δ 8.17 –
8.03 (m, 1H), 7.54 (ddd, J = 8.3, 7.2, 2.0 Hz, 1H), 7.50 – 7.40 (m, 2H), 7.40 – 7.14 (m, 3H), 6.89
– 6.67 (m, 2H), 6.22 (q, J = 6.5 Hz, 1H), 1.64 (d, J = 6.6 Hz, 3H).
2-[(4-Trifluoromethylphenyl)methoxy]-pyridine (1e); white crystals (75%); mp 35-36°C; 1H
NMR (300 MHz, CDCl3) δ 8.16 (dd, J=5.05, 1.36 Hz, 1H), 7.64-7.55 (m, 5H), 6.91 (dd, J=6.24,
5.15, 1H), 6.83 (d, J=8.36, 1H), 5.45 (s, 2H). 13C NMR (75 MHz, CDCl3) δ 163.2, 148.8, 141.6,
138.7, 129.8 (q, J=32.32 Hz), 127.7, 125.3, 124.2 (q, J=270.34 Hz), 117.2, 111.2, 66.4; IR (cm-1)
3020, 2943, 2888, 2550, 1931, 1824, 1613, 1596, 1572, 1511, 1467, 1434, 1419, 1363, 1324,
21
1306, 1286, 1269, 1250, 1190, 1159, 1141, 1125, 1112, 1068, 1040, 1019, 1000; HRMS (EI+)
Calcd for C13H10OF3N: 253.0715, found: 253.0710.
2-[(4-Chlorophenyl)methoxy]-pyridine (1f); yellow oil, (93%); 1H NMR (300 MHz, CDCl3) δ
8.24 – 8.06 (m, 1H), 7.59 (ddd, J = 9.0, 7.1, 2.0 Hz, 1H), 7.51 – 7.18 (m, 4H), 6.89 (ddd, J = 6.9,
5.1, 0.8 Hz, 1H), 6.80 (dd, J = 8.4, 0.7 Hz, 1H), 5.35 (s, 2H).
NO
Et
2-(Ethylphenylmethoxy)-pyridine (1g); colorless oil (96%); 1H NMR (300 MHz, CDCl3) δ
8.14 – 8.00 (m, 1H), 7.52 (ddd, J = 8.4, 7.2, 2.0 Hz, 1H), 7.46 – 7.36 (m, 2H), 7.35 – 7.16 (m,
3H), 6.77 (ddd, J = 8.4, 5.9, 4.8 Hz, 2H), 5.98 (t, J = 6.6 Hz, 1H), 2.19 – 1.78 (m, 2H), 0.95 (t, J
= 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 163.4, 146.9, 142.0, 138.5, 128.1, 127.2, 126.5,
116.5, 111.4, 77.7, 30.1, 10.0; IR (cm-1) 2970, 2250, 1595, 1569, 1471, 1431, 1361, 1309, 1286,
1269, 1250, 1205, 1143, 1083, 1044; HRMS (CI+) Calcd for [C14H16ON]+: 214.1232, found:
214.1232.
2-(Cyclohexylphenylmethoxy)-pyridine (1h); colorless oil (63%); 1H NMR (300 MHz, CDCl3)
δ 8.03 (dd, J = 5.3, 1.4 Hz, 1H), 7.54 – 7.41 (m, 1H), 7.41 – 7.33 (m, 2H), 7.28 (dd, J = 11.2, 4.1
Hz, 2H), 7.24 – 7.14 (m, 1H), 6.79 – 6.64 (m, 2H), 5.81 (d, J = 7.3 Hz, 1H), 2.11 – 1.37 (m, 6H),
1.36 – 0.84 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 13C NMR (75 MHz, CDCl3) δ 163.6, 146.9,
140.9, 138.4, 127.9, 127.2, 127.1, 116.4, 111.2, 80.7, 43.8, 29.2, 29.0, 26.4, 26.1, 26.0; IR (cm-1)
22
3032, 2927, 2853, 1596, 1569, 1470, 1451, 1430, 1357, 1310, 1285, 1268, 1251, 1141, 1098,
1082, 1042; HRMS (CI+) Calcd for [C18H22ON]+: 268.1701, found: 268.1693.
2-(tert-Butylphenylmethoxy)-pyridine (1i); white crystals (51%); mp 61-62°C; 1H NMR (300
MHz, CDCl3) δ 7.94 (dd, J = 4.9, 1.0 Hz, 1H), 7.54 – 7.36 (m, 1H), 7.36 – 7.26 (m, 2H), 7.16
(tdd, J = 14.1, 6.0, 1.3 Hz, 3H), 6.76 – 6.60 (m, 2H), 5.67 (s, 1H), 0.93 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 163.6, 147.0, 139.5, 138.4, 128.0, 127.3, 127.0, 116.4, 111.2, 83.5, 35.5, 26.2.
IR (cm-1) 3031, 2956, 2870, 1593, 1570, 1470, 1453, 1430, 1393, 1363, 1308, 1283, 1267, 1203,
1184, 1141, 1080, 1043, 1028; HRMS (CI+) Calcd for [C16H20ON]+: 242.1545, found: 242.1541.
NO
Ph
2-(Diphenylmethoxy)-pyridine (1j); white crystals (99%); mp 53-54°C; 1H NMR (300 MHz,
CDCl3) δ 8.14 – 8.04 (m, 1H), 7.59 – 7.49 (m, 1H), 7.44 (d, J = 7.2 Hz, 4H), 7.38 – 7.18 (m, 6H),
6.94 – 6.71 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.9, 146.9, 141.5, 138.6, 128.3, 127.4,
127.2, 116.9, 111.6, 77.4. IR (cm-1) 3062, 3030, 1951, 1595, 1569, 1495, 1468, 1454, 1429, 1306,
1283, 1265, 1247, 1186, 1141, 1101, 1080, 1041; HRMS (CI+) Calcd for [C18H16ON]+:
262.1232, found: 262.1239.
Phenyl(2-pyridyl)methanol (2a); white crystals, (85%); 1H NMR (300 MHz, CDCl3) δ 8.52 (d,
J=4.20 Hz, 1H), 7.58 (dt, J=7.72, 1.68 Hz, 1H), 7.39-7.13 (m, 7H), 5.74 (s, 1H), 5.43 (broad s,
1H).
23
α-(2-Methoxyphenyl)2-pyridinemethanol (2b); colorless crystals, (48%); mp 61-62°C; 1H
NMR (300 MHz, CDCl3) δ 8.53 (d, J=4.76 Hz, 1H), 7.58 (dt, J=7.74, 1.69 Hz, 1H), 7.32-7.13 (m,
4H), 6.95-6.88 (m, 2H), 6.20 (s, 1H), 3.85 (s, 3H); 13C NMR (300 MHz, CDCl3) δ 161.2, 156.6,
147.7, 136.6, 131.6, 128.7, 127.7, 122.1, 121.2, 120.9, 110.7, 69.1, 55.4; IR (cm-1) 3132, 3008,
2840, 1595, 1570, 1488, 1475, 1460, 1440, 1332, 1288, 1271, 1238, 1214, 1188, 1150, 1113,
1092, 1040, 1024, 1005; HRMS (ESI+) Calcd for C13H13O2NNa: 238.0844, found: 238.0856.
α-(4-Methoxyphenyl)2-pyridinemethanol (2c); colorless crystals, (33%); 1H NMR (300 MHz,
CDCl3) δ 8.56 (d, J=4.88Hz, 1H), 7.61 (dt, J=7.70, 1.70 Hz, 1H), 7.30-7.26 (m, 2H), 7.21-7.12
(m, 2H), 6.89-6.84 (m, 2H), 5.71 (s, 1H), 5.22 (broad s, 1H), 3.78 (s, 3H).
α-Methyl-α-phenyl-2-pyridinemethanol (2d); light yellow oil, (98%); 1H NMR (300 MHz,
CDCl3) δ 8.52 (d, J = 4.9 Hz, 1H), 7.65 (td, J = 7.7, 1.7 Hz, 1H), 7.48 (d, J = 7.1 Hz, 2H), 7.33-
7.16 (m, 5H), 5.85 (s, 1H), 1.93 (s, 3H).
24
α-(4-Chlorophenyl)-2-pyridinemethanol (2f); off-white solid, (70%); 1H NMR (300 MHz,
CDCl3) δ 8.57 (d, J = 4.9 Hz, 1H), 7.64 (td, J = 7.7, 1.7 Hz, 1H), 7.31 (s, 4H), 7.22 (dd, J = 7.3,
5.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 5.72 (d, J = 2.5 Hz, 1H), 5.33 (d, J = 3.5 Hz, 1H).
α-Ethyl-α-phenyl-2-pyridinemethanol (2g); white crystals, (86%); mp 75-76°C; 1H NMR (300
MHz, CDCl3) δ 8.43 (dd, J = 4.9, 0.6 Hz, 1H), 7.57 (td, J = 8.0, 1.7 Hz, 1H), 7.51 – 7.39 (m, 2H),
7.34 – 6.94 (m, 5H), 5.87 (s, 1H), 2.56 – 1.92 (m, 2H), 0.79 (t, J = 7.3 Hz, 3H); 13C NMR (300
MHz, CDCl3) δ 163.6, 147.2, 146.4, 136.9, 128.2, 126.8, 126.0, 121.9, 120.5, 77.3, 33.8, 8.0; IR
(cm-1) 3360, 3058, 2969, 2936, 2878, 1591, 1570, 1492, 1467, 1447, 1432, 1391, 1323, 1294,
1194, 1153, 1134, 1090, 1062, 1031; HRMS (CI+) Calcd for [C14H16ON]+: 214.1232, found:
214.1227.
N
OH
α-Cyclohexyl-α-phenyl-2-pyridinemethanol (2h); colorless oil, (20%); 1H NMR (300 MHz,
CDCl3) δ 8.45 (d, J = 4.3 Hz, 1H), 7.65 (dd, J = 10.6, 4.4 Hz, 3H), 7.46 (dd, J = 8.1, 0.9 Hz, 1H),
7.40 – 7.23 (m, 2H), 7.23 – 7.03 (m, 2H), 6.12 (s, 1H), 2.40 (dd, J = 15.0, 6.6 Hz, 1H), 1.84 –
1.46 (m, 4H), 1.46 – 0.89 (m, 6H); 13C NMR (300 MHz, CDCl3) δ 163.3, 146.8, 145.9, 137.0,
128.1, 126.4, 125.9, 121.7, 120.4, 79.4, 77.2, 46.3, 26.9, 26.7, 26.6, 26.4; IR (cm-1) 3341, 3057,
2930, 2851, 1713, 1591, 1571, 1491, 1467, 1446, 1432, 1392, 1195, 1173, 1153, 1124, 1095,
1068, 1033; HRMS (CI+) Calcd for [C18H22ON]+: 268.1701, found: 268.1696.
25
N
OH
α, α-Diphenyl-2-pyridinemethanol (2j); white solid, (86%); mp 102-103°C; 1H NMR (300
MHz, CDCl3) δ 8.60 (d, J = 4.3 Hz, 1H), 7.65 (td, J = 7.7, 1.7 Hz, 1H), 7.45 – 7.19 (m, 11H),
7.12 (d, J = 7.9 Hz, 1H), 6.30 (s, 1H); 13C NMR (300 MHz, CDCl3) δ 163.2, 147.7, 146.1, 136.4,
128.1, 127.9, 127.3, 122.9, 122.3, 80.8; IR (cm-1) 3376, 3058, 1590, 1572, 1490, 1466, 1447,
1432, 1375, 1169, 1039; HRMS (CI+) Calcd for [C18H16ON]+: 262.1232, found: 262.1232.
26
27
28
29
29
30
31
32
32
33
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
52
REARRANGEMENT OF BEZYLOXYPYRIDINES---PYRIDINE-
ETHER
In this part, we will present indirect evidence of a unique and unexpected carbolithiation
of an enol ether (pyridyl ether 7, Figure 18, Equation 18a), 34 in which organolithium
nucleophiles35 add inter-molecularly across the electron-rich alkene in a manner opposite the
normal polarization preferences of an enol ether (contra-electronically). 36 This observation
provides insight into the unusual behavior of highly reactive species 37 , 38 and reveals an
alternative entry into our reported anionic rearrangement of benzyloxypyridines (Figure 18,
Equation 18b).39
O N
1g [Ib] 2g
Figure 18: Formation of Pyridyl Alcohol from Enol Ether 7 and Benzyloxypyridine 1g
53
4.1 The chemistry of enol ethers
Enol ethers have shown reactivity toward different electrophiles and it is believed to be
due to the high electron density on the β-C atom (Figure 19). As a result, the fundamental types
of reactions for enol ethers are (1) Cationic polymerization in the presence of Lewis acids
(Figure 20, Equation 20a), and (2) Reactions with X — Y type compounds resulting in bond
formation between the less electronegative atom (Y) of the compound and the β-C atom of the
enol ether (Figure 20, Equation 20b).40 One typical example for the second type of reaction for
enol ethers is the addition of alcohols to enol ethers under acidic condition to form acetals
(Figure 20, Equation 20c).
R3
H
Figure 19: High Electron Density on the β-C in Enol Ethers
O
54
4.2 Overview of the new pyridine directed organolithium addition to enol ether 7
The observation of this new type of reaction for enol ethers is as follows: addition of 1.3
equiv of n-butyllithium to a solution of -pyridyloxy-styrene 7 in THF provides an 84% yield of
tertiary pyridyl carbinol 8a (Figure 21, Equation 21a). To explain this, one must account for (1)
C–C bond formation at the -carbon of the enol ether, and (2) migration of the pyridyl group
from oxygen to the -carbon.
O N
7 8a[Ia]
Figure 21: The Formation of Pyridyl Alcohol from Enol Ether 7 and Benzyloxypyridine 1g.
Given that directed metallation of benzyl pyridyl ethers triggers an anionic rearrangement
to give tertiary pyridyl carbinols (e.g., Figure 21, Equation 21b),39 the simplest explanationv
involves carbolithiation of enol ether 7 (7 [Ia], Figure 21, Equation 21a).
The presumed carbolithiation (7 [Ia]) is the first example to our knowledge of the enol
ether -system reacting with an electron-rich (nucleophilic) reagent. Moreoever, the nucleophilic
attack occurs at the more electron-rich terminus of the enol ether.vi,vii
v Ockham’s razor favors the simplest explanation, but it is not an irrefutable principle of logic. vi Calculations at the B3LYP 6-31+G(d,p) level suggest that the pyridyloxy group, like the
methoxy group, is electron-releasing. Although the pyridyloxy group is a weaker donor than
55
The contra-electronic organolithium addition to 7 proceeded with the exclusion of
alternative potential reaction pathways (Figure 23). Namely, pyridine-directed carbolithiation
could be envisioned to occur in alignment with the polarization of enol 1, but the expected
products of such a process (9 and 10, Equation 23a, arising from -elimination of the lithium
alkoxide) could not be detected. Another “reasonable” reaction process would be for the
alkyllithium reagent to attack the electron-deficient pyridine ring (addition at C2, followed by
elimination of the enolate, Figure 23, Equation 23b). Although nucleophilic aromatic
substitutions at the 2-position of pyridine are well known, no such products are observed in this
process.
methoxy, the majority (51.46%) of the alkene π-electron density is localized near the β-carbon
of 7 (Fig. 22). A similar pattern is calculated for [IV], after complexation of the alkyllithium.
Figure 22: Calculated π-bond polarization (in italics) and selected net atomic charges (in
bold) for 2-pyridyloxy-styrenes 7, complex [IV], and -methoxystyrene (18).
vii This unusual reaction would not be classified as an “umpolung” process. The term
“umpolung” (meaning, “reversed polarity”) refers to an altered form of a common functional
group that displays reactivity opposite to that of the normal pattern (e.g., lithiated 1,3-dithiane
vs. aldehyde). In contrast, Equation 1 in Figure 21 represents a rare example in which the
unaltered functional group — in this case, an enol ether — displays reactivity opposite to the
expected pattern. For discussion on umpolung reactivity strategies, see: D. J. Ager, In
Umpoled Synthons: A Survey of Sources and Uses in Synthesis, (Eds.: T. A. Hase), John
Wiley & Sons, New York, 1987, pp. 19-72.
56
Figure 23: Evidence Part I for the Contra-electronic Organolithium Addition to α-(2- Pyridyloxy)-styrene 7
The central importance of the 2-pyridyloxy group in directing the alkyllithium addition to
7 is supported by the control experiments shown in Figure 24. Although carbolithiation of
styrene derivatives is known,41 this is not an example of a phenyl substitutent overriding the
normal reactivity profile of an enol ether. The 2-pyridyloxy group, not the phenyl, controls the
regioselectivity of the process: n-butyllithium reacts with stilbene derivative 13 (Figure 24,
Equation 24c) to produce tertiary alcohol 14 (i.e., by the addition / rearrangement process, Figure
24, Equation 24a) to the exclusion of 10, the expected product of regioisomeric addition and
elimination (Figure 24, Equation 24b). 4-Pyridyloxy analogue 16, in which pyridine
complexation does not produce a proximity effect, does not undergo the same addition /
rearrangement process (Figure 24, Equation 24d). Instead, starting material is recovered along
with small amounts of products derived from addition of n-butyllithium to the 2-position of
pyridine. Likewise and as expected, -methoxystyrene42 (18) is completely unreactive under
these conditions (Figure 24, Equation 24e).
57
Figure 24: Evidence Part II for the Contra-Electronic Organolithium Addition to α-(2- Pyridyloxy)-styrene
58
These data, coupled with our earlier report (Figure 25, Equation 25b),39 support the
reaction pathway outlined in Figure 25, Equation 1: pyridine-directed addition of n-butyllithium
to enol ether 7 triggers anionic rearrangement of the resulting -(2-pyridyloxy)benzyllithium,
[Ia].
1g [Ib] 2g
Figure 25: The Formation of Pyridyl Alcohol from Enol Ether 7 and Benzyloxypyridine 1g.
4.4 Proposed mechanisms for the contra-electronic addition
In considering reasonable mechanisms for this unusual addition / rearrangement sequence
(7 8), we favor a process in which carbolithiation (7 [I], Figure 26) leads directly into the
previously reported anionic rearrangement ([I] 8). To explain the apparently contra-electronic
carbanion addition, it is helpful to invoke the electron-transfer properties of highly reactive
organolithium nucleophiles.43 Precomplexation between the lithium reagent and the pyridine
nitrogen ([IV], Figure 26) produces the proximity effect44 necessary for directed carbolithiation,
which is thermodynamically favorable.viii We postulate that carbolithiation of enol ether 7 may
viii The relative energies of alkyllithium [IV], benzyllithium [I], and lithium alkoxide [VII] were
calculated at the B3LYP 6-31+G(d,p) level of theory (R = n-Bu, Fig. 27). Both the addition
59
followed almost instantaneously by radical recombination to [I]. The observed regioselectivity
would then be consistent with radical recombination ([V] [I]) ix guided by sterics and/or
proximity effects. Pyridyloxylithium [I] undergoes anionic rearrangement, as described
previously.
Ph
pyridine migration
ref 39
R[VI]
N Li
and the rearrangement appear to be highly exothermic. We thank a referee for suggesting that
we examine the energetics of the conversion of [IV] [I] [VII].
Fig. 27 Relative energies calculated for [IV], [I], and [VII].
ix A more concerted process, in which radical anion [V] undergoes the anionic rearrangement
directly without generating -pyridyloxy-benzyllithium [I], cannot be ruled out at this time.
60
Figure 26: Postulated Mechanism: Alkyllithium Addition (7 [I]) Triggers Anionic Rearrangement ([I] 8). 4.5 Preparation of -(2-pyridyloxy)-styrene 7 and scope of the nucleophilic addition
-Pyridyloxystyrene 7 was prepared as shown in Figure 28. Oxidation of diethylene
glycol methyl ether and addition of phenylmagnesium bromide to the resulting aldehyde
provided benzyl alcohol derivative 20, which was converted into pyridyl ether 21 using
nucleophilic aromatic substitution of 2-chloropyridine. 45 LDA-promoted elimination of
2-methoxyethanol from 21x provides -pyridyloxystyrene 7.
Figure 28: Preparation of -(2-Pyridyloxy)styrene (7)
A brief screening of organolithium nucleophiles revealed a correlation between
organolithium reactivity and reaction efficiency (Table 4). Methyllithium reacted with 7 along x Incidentally, this reaction was originally designed and performed as a competition experiment
between E2 elimination and the anionic rearrangement described previously39. It shows, not
surprisingly, that elimination of the lithium alkoxide is faster than the anionic rearrangement
(Figure 25, Equation 2). In one compromised run of this competition experiment, we used LDA
that was contaminated with a small amount n-butyllithium, which resulted in isolation of 8a and
identification of the contra-electronic alkyllithium addition reaction.
61
the presumed carbolithiation and anionic rearrangement pathway to give 8b in 84% yield (Table
4, Entry 1), which is comparable to the 84% yield observed in the reaction of 7 with
n-butyllithium (Table 4, Entry 3). Methylmagnesium bromide, on the other hand, was unreactive
under similar conditions (Table 4, Entry 2). The more reactive secondary and tertiary
butyllithium isomers produced higher yields of tertiary alcohol product:xi s-BuLi, 86%, Table 4,
Entry 4; t-BuLi, 97%, Table 4, Entry 5. Reaction of 7 with phenyllithium, which is less
nucleophilic than most alkyllithium reagents, gave rise to alcohol 8e in a relatively modest 75%
yield (Table 4, Entry 6), and the hydride reagent produced a mixture of products including
acetophenone (11), which presumably arises from hydride addition to pyridine at C2 (Figure 29).
Table 4 Scope of the nucleophilic addition to -pyridyloxystyrene 7.a
Styrene 7 in THF treated with organometallic reagent at room temperature under nitrogen. b No
a
reaction. c 1H NMR spectroscopic analysis of the crude reaction mixture revealed a complex mixture of products, including starting material and acetophenone (Figure 29).
xi Similar reactivity trends have been documented for other directed carbolithiation reactions; see
ref 34a, ref 34d, and ref 37.
62
igure 29: No Nucleophilic Aromatic Substitution with n-Butyllithium
In summary, organolithium addition to an enol ether has been observed within the context
of
F
a previously reported anionic rearrangement of lithiated benzyl pyridyl ethers.6 Specifically,
pyridine-directed, contraelectronic addition of reactive alkyllithium reagents to
-(2-pyridyloxy)-styrene (7) triggers the anionic rearrangement to provide tertiary pyridyl
carbinols. We postulate a mechanism in which the organolithium reagent attacks 7 in a dipole-
opposed (contraelectronic) fashion, perhaps via a single electron transfer mechanism, with the
carbanionic moiety reacting at the more electron-rich terminus of the enol ether.
63
General information
1H-NMR and 13C-NMR spectra were recorded on a 400 MHz spectrometer using CDCl3 as the
deuterated solvent. The chemical shifts (δ) are reported in parts per million (ppm) relative to
internal TMS (0 ppm for 1H NMR) or the residual CDCl3 peak (7.26 ppm for 1H NMR, 77.0 ppm
for 13C NMR). The coupling constants (J) were reported in Hertz (Hz). IR spectra were recorded
on an FT-IR spectrometer. Mass spectra were recorded using electrospray ionization (ESI) or
electron ionization (EI) techniques. All chemicals were used as received unless otherwise stated.
The solvents used for the reactions were all freshly distilled. Glassware, NMR tubes, stir bars,
needles, and syringes were dried overnight in an oven heated at 120 °C. All reactions were
performed under nitrogen atmosphere unless otherwise noted. Neutral organic compounds were
purified by flash column chromatography using silica gel F-254 (230-499 mesh particle size).
Yields refer to isolated material judged to be >95% pure by 1H NMR spectroscopy.
General experimental procedures & Characterization data
-[(2-Methoxyethoxy)methyl]-Benzenemethanol (20): To a DMF (6 ml) solution of oxalyl
chloride (0.16 ml, 1.83 mmol) was added DMSO (0.28 ml, 3.66 mmol) at -60 °C drop by drop,
followed by di(ethylene glycol) methyl ether (0.2 ml, 1.67 mmol) drop by drop. The resulting
solution was stirred for 15 min before triethylamine (1.16 ml, 8.32 mmol) was added. The
64
reaction was then warmed up to room temperature and stirred for another 3 hours. The reaction
mixture was then diluted with water (20 ml) and extracted with ethyl acetate (3 x 10 ml). The
combined organics were washed with saturated aqueous sodium chloride (20 ml), dried over
Na2SO4, filtered and concentrated under reduced pressure to give a colorless oil. The crude
product was dissolved in dry THF (4 ml) and phenylmagnesium bromide (2 ml, 1 M, 1.2 equiv)
was added drop by drop at room temperature with subsequent stirring for 1 hour. The reaction
mixture was quenched with water (10 ml) and extracted with ethyl acetate (3 x 10 ml). The
combined organics were washed with saturated aqueous sodium chloride (10 ml), dried over
Na2SO4, filtered and concentrated under reduced pressure to give a colorless oil. The crude
product mixture was purified by chromatography on silica gel (elution with 50% EtOAc/Hexanes)
to provide 111 mg of alcohol 20 as colorless oil (34% yield over two steps); 1H NMR (400 MHz,
CDCl3) δ 7.37-7.26 (m, 5H), 4.93 (dd, 1H, J=9.30, 2.82 Hz), 3.78-3.67 (m, 3H), 3.62-3.56 (m,
2H), 3.47 (t, 1H, J=9.72 Hz), 3.41 (s, 3H), 3.25 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 140.1
128.3 127.7 126.1 77.2 72.7, 71.9, 70.6, 59.1; IR (cm-1) 3415, 3030, 2890, 1605, 1494,
1452, 1356, 1325, 1244, 1199, 1096, 1027; HRMS (ESI+) Calcd for C11H16O3Na: 219.1023,
found: 219.0997.
2-[2-(2-Methoxy-ethoxy)-1-phenyl-ethoxy]-pyridine (21): We prepared benzyloxy-pyridine 21
by a modified version of a procedure first reported in 1980: A toluene solution of benzyl alcohol
20 (0.5 M, 1.0 equiv), 2-chloropyridine (1.1 equiv), KOH (3.3 equiv), and 18-crown-6 (0.05
equiv) was heated at reflux until all of the alcohol was consumed. The resulting mixture was
cooled to room temperature and then diluted with H2O. The mixture was extracted with EtOAc.
The combined organic extract was washed with H2O until the aqueous layer becomes neutral,
then with brine and dried (Na2SO4), filtered, concentrated under vacuum, and purified on silica
gel to yield benzyloxypyridine 21 in 81% yield as a colorless oil. 1H NMR (400 MHz, CDCl3) δ
65
8.05 (dd, 1H, J=1.32, 4.88 Hz), 7.54-7.50 (m, 1H), 7.45-7.43 (m, 2H), 7.33-7.23 (m, 3H), 6.83-
6.77 (m, 2H), 6.33 (dd, 1H, J=7.84, 3.72 Hz), 3.97-3.92 (m, 1H), 3.82-3.78 (m, 1H), 3.71-3.70
(m, 2H), 3.52-3.49 (m, 2H), 3.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.1, 146.9, 139.0,
138.5, 128.3, 127.6, 126.7, 116.8, 111.4, 75.4, 75.0, 71.9, 70.7, 59.0; IR (cm-1) 2876, 1595, 1570,
1469, 1454, 1430, 1357, 1308, 1270, 1250, 1199, 1104, 1050, 1028; HRMS (EI+) Calcd for
C16H19NO3: 273.1365, found: 273.1361.
7
2-[(1-phenylethenyl)oxy]-pyridine (7): A solution of LDA (14.3 ml, 0.5 M in THF, 1.1 equiv)
was added to a solution of benzyloxypyridine 21 (1.77g, 6.48mmol) in THF (12 mL) at room
temperature dropwise, and the reaction mixture was stirred at room temperature for 1.5 hours.
The reaction mixture was quenched with water (20 ml) and extracted with ethyl acetate (3 x 20
ml). The combined organics were washed with saturated aqueous sodium chloride (20 ml), dried
over Na2SO4, filtered and concentrated under reduced pressure to give a colorless oil. The crude
product mixture was purified by chromatography on silica gel (elution with 10% EtOAc/Hexanes)
to provide 856 mg of pyridyl ether 7 in 67% yield as colorless oil. 1H NMR (400 MHz, CDCl3) δ
8.17 (d, 1H, J=3.32 Hz), 7.64-7.57 (m, 3H), 7.32-7.25 (m, 3H), 6.95-6.90 (m, 2H), 5.41 (d, 1H,
J=1.72 Hz), 4.96 (d, 1H, J=1.72 Hz); 13C NMR (100 MHz, CDCl3) δ 163.2, 156.2, 148.0, 139.4,
134.9, 128.7, 128.4, 125.6, 118.4, 111.5, 99.2; IR (cm-1) 3057, 1640, 1615, 1592, 1571, 1493,
1467, 1446, 1428, 1263, 1239, 1183, 1142, 1095, 1076, 1043, 1027; HRMS (EI+) Calcd for
C13H11NO: 197.0841, found: 197.0842.
2-(1,2-Diphenyl-vinyloxy)-pyridine (13): To a solution of benzoin methyl ether (5 g, 22.1
mmol) in THF (20 ml) was added lithium aluminum hydride powder (282.3 mg, 7.1mmol) in
portions over 5 min at 0 °C. The reaction mixture was then warmed up to room temperature,
stirred for 30 min, and then quenched with H2O (20 ml). The reaction mixture was extracted with
ethyl acetate (3 x 20 ml). The combined organics were washed with saturated aqueous sodium
chloride (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a
colorless oil. The crude product mixture was purified by chromatography on silica gel (elution
with 20% EtOAc/Hexanes) to provide 4.90g of white crystals tentatively assigned as 2-methoxy-
1,2-diphenyl-ethanol (97% yield). A THF solution of this benzyl alcohol (2.08 g, 9.09 mmol), 2-
chloropyridine (8.54 ml, 90.9 mmmol), KOH (1.68g, 30.01 mmol), and 18-crown-6 (120.2 mg,
0.045 mmol) was heated at reflux overnight. The resulting mixture was cooled to room
temperature and then diluted with H2O (20 ml). The mixture was extracted with EtOAc (3 x 20
ml). The combined organic extract was washed with H2O until the aqueous layer becomes
neutral, then with brine (20 ml) and dried (Na2SO4), filtered, concentrated under vacuum, and
purified on silica gel (10% EtOAc/Hexanes) to yield 2.55g of a colorless oil tentatively assigned
as 2-(2-methoxy-1,2-diphenyl-ethoxy)-pyridine (92% yield). A solution of this benzyloxy
pyridine solution (2.55g, 8.34mmol) in THF (10 ml) was treated with a solution of LDA in THF
(1.1 equiv) at room temperature dropwise, and the reaction mixture was stirred at room
temperature for 5 hours. The reaction mixture was quenched with water (20 ml) and extracted
with ethyl acetate (3 x 20 ml). The combined organics were washed with saturated aqueous
sodium chloride (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to
give a colorless oil. The crude product mixture was purified by chromatography on silica gel
(elution with 15% EtOAc/Hexanes) to provide 1.72g of enol ether 13 in 75% yield as a white
crystals. 1H NMR (400 MHz, CDCl3) δ 8.14-8.13 (m, 1H), 7.64-7.61 (m, 5H), 7.40-7.17 (m, 6H),
6.98-6.88 (m, 2H), 6.74 (s, 1H); HRMS (EI+) Calcd for C19H15NO: 273.1154, found: 273.1149.
67
1,2-Diphenyl-1-pyridin-2-yl-hexan-1-ol (14): Enol ether 13 (50mg, 0.18mmol, 1.0 equiv) was
dissolved in THF (1ml) in a 5 ml round bottom flask at room temperature. To this solution was
added n-BuLi (80 l, 1.8M in hexanes, 1.3 equiv) dropwise, and the resulting dark brown
solution was stirred over night. The resulting mixture was diluted with H2O (5 mL) and extracted
with EtOAc (4 x 5 mL). The combined organic extracts were then washed with saturated
aqueous sodium chloride (10ml), dried (Na2SO4), filtered, concentrated under vacuum, and
purified on silica gel (15% EtOAc/Hexanes) to yield pyridine alcohol 14 in 25% yield as a 2.4:1
mixture of diastereomers, white solid, mp 116-118°C; 1H NMR (400 MHz, CDCl3) δ 8.52 (d, 1H,
J=4.80 Hz), 8.10 (d, 1H, J=4.80 Hz), 7.79-7.68 (m, 4H), 7.50-7.36 (m, 7H), 7.31-7.23 (m, 2H),
7.21-6.87 (m, 13H), 6.36 (s, 1H), 6.09 (s, 1H), 3.68-3.63 (m, 2H), 2.05-1.84 (m, 2H), 1.79-1.70
(m, 1H), 1.27-0.98 (m, 9H), 0.76-0.68 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 163.4 162.3,
147.2, 146.2, 145.9, 145.8, 141.2, 140.4, 137.1, 136.4, 130.2, 130.0, 128.4, 127.6, 127.43, 127.36,
126.8, 126.15, 126.12, 126.01, 125.98, 125.92, 122.0, 121.3, 121.1, 120.3, 80.3, 79.9, 77.2, 54.6,
54.3, 30.5, 30.1, 30.0, 29.8, 22.6, 13.97, 13.91; IR (cm-1) 3290, 3061, 2934, 2858, 1593, 1571,
1494, 1446, 1434, 1405, 1127, 1063, 1001; HRMS (ESI+) Calcd for C23H26NO: 332.2014, found:
332.2024.
4-(1-Phenyl-vinyloxy)-pyridine (16): A toluene solution of benzyl alcohol 20 (0.5 M, 1.0
equiv), 4-chloropyridine (3 equiv), KOH (6.6 equiv), and 18-crown-6 (0.05 equiv) was heated at
reflux for 2 days. The resulting mixture was cooled to room temperature and then diluted with
H2O. The mixture was extracted with EtOAc. The combined organic extract was washed with
H2O until the aqueous layer becomes neutral, then with brine and dried (Na2SO4), filtered,
68
concentrated under vacuum, and purified on silica gel to yield a colorless oil tentatively assigned
as 4-[2-(2-methoxy-ethoxy)-1-phenyl-ethoxy]-pyridine (53% yield). A solution of this
benzyloxypyridine (73.6 mg, 0.269mmol) in THF at room temperature was treated with solution
of LDA in THF (1.1 equiv) dropwise. The reaction mixture was stirred at room temperature
overnight and then quenched with water (5 ml) and extracted with ethyl acetate (3 x 5 ml). The
combined organics were washed with saturated aqueous sodium chloride (5 ml), dried over
Na2SO4, filtered and concentrated under reduced pressure to give a colorless oil. The crude
product mixture was purified by chromatography on silica gel (elution with 30% EtOAc/Hexanes)
to provide 23.2 mg of pyridyl ether 16 in 44% yield as colorless oil. Colorless oil; 1H NMR (400
MHz, CDCl3) δ 8.47 (s, 2H), 7.56-7.53 (m, 2H), 7.36-7.34 (m, 3H), 6.96-6.95 (m, 2H), 5.44 (d,
1H, J=1.96 Hz), 4.96 (d, 1H, J=1.96 Hz); 13C NMR (100 MHz, CDCl3) δ 163.8, 156.2, 151.4,
133.7, 129.3, 128.7, 125.5, 112.7, 99.5; IR (cm-1) 3033, 1637, 1584, 1493, 1446, 1417, 1257,
1206, 1097, 1076, 1026; HRMS (EI+) Calcd for C13H11NO: 197.0841, found: 197.0846.
General procedure for the addition of organolithium reagents to enol ether 7: Enol ether 7
(20 mg, 1 equiv) was dissolved in 1 mL of THF at room temperature, followed by addition of the
organolithium reagent (1.3 equiv) drop by drop. The reaction mixture was stirred overnight or
until TLC analysis of the reaction mixture showed complete consumption of the enol ether. The
reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (4 x 5 mL). The
combined organic extracts were washed with brine, dried (Na2SO4), filtered, concentrated under
vacuum, and purified on silica gel to yield pyridine alcohols 8a, 8b, 8c 8d and 8e.
HO
n-Bu
N
8a
α-Pentyl-α-phenyl-2-pyridinemethanol (8a): Colorless oil (84%); 1H NMR (400 MHz, CDCl3)
δ 8.50 (d, 1H, J=4.84 Hz), 7.66-7.61 (m, 1H), 7.54-7.52 (m, 2H), 7.34-7.29 (m, 3H), 7.22-7.14
(m, 2H), 5.96 (s, 1H), 2.31-2.15 (m, 2H), 1.46-1.11 (m, 6H), 0.83 (t, 3H, J=6.90 Hz); 13C NMR
69
(100 MHz, CDCl3) δ 163.8, 147.2, 146.6, 136.9, 128.2, 126.7, 125.9, 121.9, 120.4, 77.1, 41.2,
32.2, 23.2, 22.5, 14.0; IR (cm-1) 3362, 3058, 2953, 2929, 2869, 1591, 1571, 1493, 1467, 1446,
1432, 1391, 1293, 1188, 1152, 1134, 1089, 1065, 1033; HRMS (EI+) Calcd for C17H21NO:
255.1623, found: 255.1629.
3-Methyl-1-phenyl-1-pyridin-2-yl-pentan-1-ol (8c): The reaction was done in 10 min and gave
pyridyl alcohol 8c in 86% yield as a 2.4:1 mixture of diastereomers, colorless oil; 1H NMR (400
MHz, CDCl3) δ 8.52 (s, 1H), 8.51 (s, 1H), 7.68-7.62 (m, 2H), 7.59-7.57 (m, 4H), 7.39-7.31 (m,
6H), 7.24-7.16 (m, 4H), 6.08 (s, 1H), 6.03 (s, 1H), 2.44-2.40 (m, 1H), 2.33-2.28 (m, 1H), 2.24-
2.19 (m, 1H), 2.12-2.07 (m, 1H), 1.68-1.38 (m, 3H), 1.34-1.05 (m, 3H), 0.92 (d, 3H, J=6.68 Hz),
0.85 (t, 3H, J=7.40 Hz), 0.77 (t, 3H, J=7.40 Hz), 0.71 (d, 3H, J=6.68 Hz); 13C NMR (100 MHz,
CDCl3) δ 164.2, 164.1, 147.4, 147.2, 147.1, 147.0, 136.84, 136.79, 128.14, 128.13, 126.7, 125.93,
125.90, 121.9, 120.8, 120.7, 77.6, 47.7, 47.4, 31.3, 30.9, 30.5, 30.2, 21.2, 20.6, 11.22, 11.18; IR
(cm-1) 3352, 3058, 2958, 2926, 2873, 1591, 1571, 1493, 1465, 1446, 1432, 1392, 1293, 1188,
1153, 1137, 1089, 1065, 1033; HRMS (EI+) Calcd for C17H21NO: 255.1623, found: 255.1622.
3,3-Dimethyl-1-phenyl-1-pyridin-2-yl-butan-1-ol (8d): The reaction was done in 10 min and
gave pyridyl alcohol 8d in 97% yield as colorless crystals; mp 83-84°C; 1H NMR (400 MHz,
CDCl3) δ 8.46 (d, 1H, J=4.80 Hz), 7.63-7.58 (m, 3H), 7.44-7.42 (m, 1H), 7.30-7.25 (m, 2H),
7.18-7.10 (m, 2H), 6.14 (s, 1H), 2.44-2.32 (m, 2H), 0.85 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
164.5, 148.5, 146.8, 136.7, 128.0, 126.4, 125.6, 121.7, 120.9, 77.4, 52.1, 32.00, 31.6; IR (cm-1)
70
3344, 3058, 2951, 2904, 1591, 1571, 1492, 1467, 1446, 1433, 1390, 1363, 1293, 1248, 1220,
1153, 1123, 1094, 1071, 1031; HRMS (EI+) Calcd for C17H21NO: 255.1623, found: 255.1630.
α-Phenyl-α-(phenylmethyl)-2-pyridinemethanol (8e): PhLi (0.11 ml, 1.8 M, 2 equiv) was
employed and the reaction gave pyridyl alcohol 8e in 75% yield as a white solid; mp 95-96°C; 1H NMR (400 MHz, CDCl3) δ 8.38 (d, 1H, J=4.88 Hz), 7.65-7.59 (m, 3H), 7.44-7.42 (m, 1H),
7.35-7.31 (m, 2H), 7.25-7.23 (m, 1H), 7.13-7.09 (m, 4H), 6.97-6.95 (m, 2H), 5.48 (s, 1H), 3.71-
3.58 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.9, 147.1, 146.2, 136.7, 136.5, 130.8, 128.2,
127.6, 127.1, 126.3, 126.2, 121.9, 121.0, 77.4, 47.2; IR (cm-1) 3342, 3059, 3029, 2924, 1590,
1571, 1495, 1469, 1446, 1433, 1392, 1293, 1188, 1153, 1117, 1090, 1063, 1032; HRMS (ESI+)
Calcd for C19H18NO: 276.1388, found: 276.1384.
71
OMe
O
HO
72
OMe
O
HO
73
H
O
Computational Analysis
ies in Hartrees and Cartesian coordinates are given for each structure as the
llowing.
All calculations were performed using Gaussian 03 software,xii and all structures were optimized
at the B3LYP 6-13+G(d,p) level. NBO conditions were used to calculate net atomic charges.
Total energ
Number x y z
6 -5.06323000 0.69118500 0.00094100
6 -3.95941500 1.55244500 -0.00204500
xii Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;
Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J.W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul,
A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara,
A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople,
J. A. Gaussian 03, Revision C.02; Gaussian: Wallingford, CT, 2004.
90
The [1,2]-anionic rearrangement of 2-benzyloxypyridine derivatives affords a variety of
α-pyridyl alcohols in good to excellent yield. This reaction may provide a new route to the
enantioselective synthesis of tertiary pyridyl alcohols. If this rearrangement process is
stereospecific, then chiral tertiary pyridyl carbinols will be available enantiospecifically from
chiral secondary alcohols (Figure 30).
Figure 30: [1,2]-Anionic Rearrangement of 2-Benzyloxypyridine and Related Pyridyl Ethers
g molecule with chiral
base
The other goal in the future is to broaden the scope of this novel reaction. We will turn
our attention to other aspects of the reaction that we still need to investigate before combining all
the findings into a full paper. A the rearrangement reaction has
previously been performed on benzyl pyrid 2 groups, but
not with substituted aromatic heter f our plan is to study which other
aromatic heterocycles can undergo this novel anionic rearrangement.
In order to test this hypothesis, we should be able to measure the e.e. value of product 2
by HPLC, chiral NMR shift reagents or any other applicable method. We will then look at
different methods for controlling absolute stereochemistry of the alcohol product. One approach
would be carrying out the rearrangement reaction on a single enantiomer starting molecule using
different bases in different solvents and at different temperatures to see if the e.e. value will be
retained. The other approach would be treating a racemic startin
/ligands to see if enantioselectivity could be introduced.
s shown above in Figure 30,
yl ethers with varied phenyl ring and R
ocycle. Thus the other part o
98
INTRODUCTION
The annulation & carbonyl extrusion strategy is a central on-going project in the Dudley
1,3-cyclohexanediones (Figure 31), reacted with a wide range of
arbanionic nucleophiles in an addition / fragmentation process to provide the desired alkynyl
etone and a metal triflate salt. The two-step sequence achieved the conversion of symmetric,
kynyl ketones, which comprised orthogonal and non-contiguous
functionalities (ketone and alkyne, Figure 32, Equation 32b). The stability of the triflate anion
(an excellent nucleofuge) enables the fragmentation process in much the same way as formation
of molecular nitrogen is a driving force in e Eschenmoser-Tanabe reaction (Figure 32,
CHAPTER SEVEN
lab. Aldingenin B was chosen as the natural product target for the application of this
methodology. In this chapter, we will introduce the annulation & carbonyl extrusion strategy and
explain how we planned to employ this methodology in the synthesis of aldingenin B.
7.1 Addition/ fragmentation of vinylogous acyl triflates (VATs)
The Dudley group reported a fragmentation strategy for generating alkynes under aprotic
conditions by exploiting the powerful nucleofugality of triflates. 46 Vinylogous acyl triflates
(VATs), typically derived from
th
R The Eschenmoser-Tanabe Fragmentation
R M
igure 32: Proposed Mechanisms for the Eschenmoser-Tanabe Fragmentation (a) and Tandem
Addition/Fragmentation of Vinylogous Acyl Triflates (b)
As shown in Figure 33, this methodology is not limited to the synthesis of alkynyl
ketones. Other nucleophiles for promoting fragmentation include enolates, hydride, and lithiated
amines, which give rise to alkynes tethered to β-keto esters, alcohols, and amides.
F
100
Triflates (VATs)
7.2 Carbonyl extrusion of dihydropyrone (DHP) triflates to yield homopropargyl alcohols
Whereas carbocyclic VATs give rise to alkynyl ketones through a tandem addition / C-C
bond cleavage process (Figure 32, Equation 32b, Figure 33), their oxacyclic analogs, 5,6-
dihydro-2-pyrone (DHP) triflates, react along a more complicated mechanistic pathway to
furnish homopropargyl alchohols (Figure 34).4 to 5,6-dihydro-2-pyrone
long the conventional
nes (path a) or undergo immediate fragmentation (path b, not observed). The former path (path
a) gives rise to acyclic triflate II, which is then subject to addition / C-C cleavage process.
Ultimately, homopropargyl alcohols arise stereospecifically from cyclic dihydropyrone triflates.
Addition of methylmagnesium bromide (2.0 equiv) in toluene emerged as the optimal choice
from careful optimization efforts.
8 Nucleophilic addition
triflates provides a tetrahedral intermediate (I) that can either break down a
li
101
Figure 34: Proposed Mechanism of Carbonyl Extrusion for DHP Triflates
Figure 35: Scope of the Carbonyl Extrusion of DHP Triflates
Carbonyl extrusion is achieved with high efficiency and generality across a range of
racemic DHP triflates (Figure 35).52 It is important to note that carbonyl extrusion does not
impact the stereochemistry of the system. Stereochemical information is retained throughout the
process, enabling one to leverage a host of powerful synthetic methods (e.g., Evans aldol, Noyori
hydrogenation, etc.) for the synthesis of homopropargyl alcohols.
This methodology will produce the most generally applicable strategy for the synthesis of
diverse homopropargyl alcohols. One current goal in the Dudley lab is to apply this annulation &
carbonyl extrusion strategy in conjunction with an innovative oxidative alkyne ketalization to
achieve a short and efficient synthesis of aldingenin B. We will explain this in detail in the
trosynthetic analysis of aldingenin B (Chapter 7.4).
re
102
in the Total Synthesis of Aldingenin B
7.3 Isolation of aldingenin B
The aldingenin family 49 of bisabolene sesquiterpenes is a collection of brominated
marine natural products50 isolated from a Brazilian strain of the red alga Laurencia aldingensis.
Red algae of the Laurencia genus produce a myriad of halogenated secondary metabolites, many
of which are useful as taxonomic markers for species identification.51 It was in this vein that the
aldingenins were isolated and characterized: as part of a taxonomic investigation of the Brazilian
species of Laurencia. In the aldingenin family, aldingenin A was isolated in 200346a, followed by
the isolation of aldingenin B, C and D in 200646b Their structures are shown in Figure 37. .
103
igure 37: Novel Sesquiterpenes Aldingenin A, Aldingenin B, Aldingenin C and Aldingenin D
olated
F
7.4 Retrosynthetic analysis of aldingenin B
Aldingenin B46b (Figure 38) caught our attention due to its compact and highly
oxygenated tetracyclic structure. As a target for stereoselective synthesis, it presents interesting
challenges with respect to the controlled oxidation and installation of complex functionality —
especially at C5 — into a relativ
O O
Figure 38: Aldingenin B (1) and -Bisabolene
Our retrosynthetic analysis of aldingenin B is presented in Figure 39. A late stage
bromoetherification is planned for installation of the C7–C11 oxane ring, leading to the
entification of tricyclic keto-ketal 3 as the core target. Figure 39 revolves around the central id
104
alkyne 2: our assembly / carbonyl extrusion strategy coupled with the innovative oxidative
lkyne ketalization would greatly simplify the chemical synthesis. The assembly / carbonyl
xtrusio
a
e n of DHP triflate 5 would produce anti-homopropagyl alcohol 4 for assembling alkyne-
diol 2 (Figure 39). The anti-homopropargyl alcohol 4 would be difficult to assemble by
conventional methods such as allenylmetal addition, acetylide opening of a terminal epoxide, or
Corey-Fuchs alkynylation.
In the forward direction, our plan is to conver
of DHP
alcohol 4 using the annulation and carbonyl extrusion sequence. Ring-closing metathesis and
asymmetric dihydroxylation under reagent control would convert 4 into the pivotal synthetic
intermediate, alkylnyl-cyclohexanediol 2. A novel oxidative cyclo-ketalization of alkyne-diol 2
is envisioned, as is discussed in the following sections (Figure 40).
Figure 40: Carbonyl Extrusion Approach to Alkyne-diol 2 from Anti-aldol Fragment 6
105
7.5 Oxidative ketalization of alkynes
As shown in the retrosynthetic analysis (Chapter 7.4, Figure 39), there are two key steps
for the synthesis of aldingenin B: (1) the assembly / carbonyl extrusion for making
-diol 2. The
arbonyl extrusion strategy has been reported previously by the Dudley lab, but precedent for the
ields, the reaction mixture was maintained as a neutral solution. This is
chieved by addition of sodium bicarbonate and magnesium sulfate, which serve as a buffer (pH
.0-7.5 initially) and neutralize hydroxide ions which are produced during the reduction of
permanganate.
homopropargyl alcohol fragment 4; (2) the oxidative keto-ketalization of alkyne
c
oxidative keto-ketalization has not been established.
Oxidation of alkynes to α-diketones can be accomplished with reagents including
permanganate ion52 and ozone53, as well as several transition metal-catalyzed processes54, etc.
The Lee group reported a general method for the oxidation of alkynes by potassium
permanganate to the corresponding 1,2-diones in aqueous acetone solutions (Figure 41).53 In
order to obtain good y
a
7
Figure 41: Oxidation of Alkynes by Potassium Permanganate in Aqueous Acetone
xidation of alkynes is ozonolysis, such as the
xidation used by the Fuganti group in the synthesis of 2-acetyl-1-pyrroline and 2-propionyl-1-
yrroline54 (the key roast-smelling odorants in food). The N-phenylacetyl amides were
oxidatively converted by ozone at low tem
Another frequently used method for the o
o
p
Me2S. The 4,5-diketones were finally converted to 2-acetyl-1-pyrroline and 2-propionyl-1-
pyrroline (Figure 42).
O
N
Figure 42: Oxidation of Alkynes by Ozonolysis
Besides the stoichiometric oxidation of alkynes, catalytic oxidations can also be achieved
by transition-metal-catalyzed oxidations. One example among these conditions is the oxidation
with hydrogen peroxide, catalyzed by methylrhenium trioxide (MTO), which was published by
the Espenson group in 1995 (Figure 43)55.
Figure 43: Oxidation of Alkynes by Transition-metal Catalysis
We were interested in potentially coupling one of these methods with ketal formation, such
that cyclization to the ketal is concerted with the alkyne oxidation. However, these methods
generally involve harsh oxidants with poor functional group tolerance and are best suited for use
on simple alkynes with aryl and/or tert-alkyl substituents. At the same time, it was tempting
retrosynthetically to unravel the keto-ketal to -diketone 7, but strategic analysis of prompted
concerns (Figure 44). -Diketones easily undergo tautomerization to enols, and the enol of C7
nd threaten to promote elimination of the
rotected C5 alcohol. Note that keto-ketal 3 cannot tautomerize (Bredt’s rule). Therefore, we
prioritized the goal of installing the C7-C8 keto-ketal of 3 without producing an intermediate
7
p
107
C7-C8 diketone, and our synthetic efforts focused on alkyne 2. As a result, we needed to avoid
the formation of α-diketone 7. Specifically, we required a method suitable for oxidation of
dialkylalkynes to -keto ketals in the presence of alcohols.
aldingenin B (1)
CH3
OH
OH
PO
R
OH
Figure 45: Oxidative Keto-ketalization of Alkynes
A thorough scan of the literature revealed a single example of the type of keto-
ketalization envisioned for the synthesis of aldingenin B. As part of a larger study on selenium-
mediated oxidations,55 Tiecco reported the oxidation of 4-octyne to 5,5-dimethoxy-4-octanone
monium peroxydisulfate and diphenyl diselenide in methanol 56 (Scheme 45, R =
ethyl; R1, R2 = n-propyl, 51% yield). Two features of this reaction were especially attractive
r our purposes: use of methanol as solvent suggests compatibility with alcohols, and the
ostulated mechanism does not involve an intermediate -diketone. However, despite significant
rest in the oxidation of alkynes, Tiecco’s methodology has received no reported follow-up
ttention in recent decades. 57 We planned to employ an intramolecular version of Tiecco’s
using am
oxidative keto-ketalization of alkynes as a simplified transformation in the synthesis of the
tricyclic core of aldingenin B (Chapter 8).
In summary, we have chosen aldingenin B as an ideal target system in which to apply
and test our assembly / carbonyl extrusion trategy. The synthesis and subsequent oxo-
ketalization of alkyne-diol 2 would rapidly build the dense polycyclic core of aldingenin B.
While our assembly / carbonyl extrusion strategy has been well studied, we knew nothing about
the oxo-ketalization. As a result, the specific goal for this dissertation was to prepare a complex
model (alkyne-diol 2) by conventional methods and establish the feasibility of the oxidative
alkyne ketalization. This will be shown in the following chapter (Chapter 8).
s
109
ALDINGENIN B
This chapter describes the completion of an aldingenin B model study that provides the
foundation for the key oxidative keto-ketalization. Proving that this unprecedented reaction is
possible was one of the central goals of my dissertation research.
8.1 Model study--- test of the oxidative ketalization step
feasibility of the proposed
xidative alkyne-diol oxo-ketalization. Model alkyne-diol 10 was prepared as a mixture of
iastereomers by a lengthy but straightforward reaction sequence (Figure 46): Diels-Alder
reaction between acrylaldehyde and isoprene afforded cyclic aldehyde 8, which was converted to
alkyne 9 via Corey-Fuchs reaction. The alkyne-ene 9 was oxidized by osmium tetroxide to yield
alkyne–diol 10 — the key compound for testing the oxidative ketalization. Alkyne-diol 10 was
subjected to the Tiecco conditions and the oxo-ketalization provided α-keto dioxolane 11 in 40%
t
e intramolecular Tiecco oxidation viably served as a simplifying
ansformation in the synthesis of aldingenin B. However, the isolated yield of 11 could not be
stablished, because the diol 10 comprised the mixture of diastereomers.
We launched a preliminary investigation to establish the
o
d
estimated yield based on the diastereomeric purity of alkyne-diol 10 (Figure 47). From this resul
we concluded that th
tr
e
110
Figure 46: Synthesis of Alkyne-diol 10 (See Chapter 10 for details)
Figure 47: Preliminary Test of the Proposed Intramolecular Alkyne-diol Oxo-ketalization (See
Chapter 10 for details)
8.2 Synthesis of the alkyne-diol 2a for the oxidative ketalization
We then started the synthesis towards the tricyclic core (2a) of aldingenin B (Figure 48).
As mentioned aboved, we plann